The present invention relates generally to methods for inhibiting cancer metastasis, and more particularly to the use of OB-cadherin peptides, and antibodies that bind such peptides, to inhibit adhesion and metastasis of circulating cancer cells.
Cancer is a significant health problem throughout the world. Although advances have been made in detection and therapy of cancer, no vaccine or other universally successful method for prevention or treatment is currently available. One reason for failure of a cancer treatment is often the growth of secondary metastatic lesions in distant organs. Therapy for metastasis currently relies on a combination of early diagnosis and aggressive treatment, which may include radiotherapy, chemotherapy or hormone therapy. However, the toxicity of such treatments limits the use of presently available anticancer agents for treatment of malignant disease. The high mortality rate for many cancers indicates that improvements are needed in metastasis prevention and treatment.
The development of less toxic antimetastatic agents would facilitate the long term treatment of latent or residual disease. Such agents could also be used prophylactically after the removal of a precancerous tumor. It has been suggested that certain agents that inhibit metastasis may function by inhibiting adhesion of cancer cells. For example, WO 97/00956 describes the use of an antibody raised against an adhesion protein on endothelial and muscle cells for inhibiting tumor metastasis.
Accordingly, there is a need in the art for the development of further methods for inhibiting cancer metastasis. The present invention fulfills these needs and further provides other related advantages.
Briefly stated, this invention provides compositions and methods for inhibiting cancer metastasis. Within certain aspects, antimetastatic agents are provided. Such agents may: (a) comprise a peptide sequence that is at least 50% identical to an OB-cadherin CAR sequence; and (b) inhibit OB-cadherin mediated cell adhesion. Certain antimetastatic agents comprise an OB-cadherin CAR sequence and are peptides ranging in size from 3 to 50, preferably from 4 to 16, amino acid residues.
Within certain embodiments, an antimetastatic agent comprises an OB-cadherin CAR sequence that is present within a cyclic peptide. Such cyclic peptides may have the formula: 
wherein W is a tripeptide selected from the group consisting of EEY, DDK and EAQ; wherein X1, and X2 are optional, and if present, are independently selected from the group consisting of amino acid residues and combinations thereof in which the residues are linked by peptide bonds, and wherein X1 and X2 independently range in size from 0 to 10 residues, such that the sum of residues contained within X1 and X2 ranges from 1 to 12; wherein Y1 and Y2 are independently selected from the group consisting of amino acid residues, and wherein a covalent bond is formed between residues Y1 and Y2; and wherein Z1 and Z2 are optional, and if present, are independently selected from the group consisting of amino acid residues and combinations thereof in which the residues are linked by peptide bonds.
Within certain specific embodiments, an antimetastatic agent as provided herein may comprise: (a) one or more OB-cadherin CAR sequences selected from the group consisting of DDK, IDDK (SEQ ID NO:37) DDKS (SEQ ID NO:38), VIDDK (SEQ ID NO:39), IDDKS (SEQ ID NO:40), VIDDKS (SEQ ID NO:41), DDKSG (SEQ ID NO:42), IDDKSG (SEQ ID NO:43), VIDDKSG (SEQ ID NO:44), FVIDDK (SEQ ID NO:45), FVIDDKS (SEQ ID NO:46), FVIDDKSG (SEQ ID NO:47), IFVIDDK (SEQ ID NO:48), IFVIDDKS (SEQ ID NO:49), IFVIDDKSG (SEQ ID NO:50), EEY, IEEY (SEQ ID NO:51), EEYT (SEQ ID NO:52), VIEEY (SEQ ID NO:53), IEEYT (SEQ ID NO:54), VIEEYT (SEQ ID NO:55), IEEYTG (SEQ ID NO:57), IEEYTG (SEQ ID NO:56), VIEEYTG (SEQ ID NO:58), FVIEEY (SEQ ID NO:59), FVIEEYT (SEQ ID NO:60), FVIEEYTG (SEQ ID NO:61), FFVIEEY (SEQ ID NO:62), FFVIEEYT (SEQ ID NO:63), FFVIEEYTG (SEQ ID NO:64), EAQ, VEAQ (SEQ ID NO:65), EAQT (SEQ ID NO:66), SVEAQ (SEQ ID NO:67), VEAQT (SEQ ID NO:68), SVEAQT (SEQ ID NO:69), EAQTG (SEQ ID NO:70), VEAQTG (SEQ ID NO:71), SVEAQTG (SEQ ID NO:72), FSVEAQ (SEQ ID NO:73), FSVEAQT (SEQ ID NO:74), FSVEAQTG (SEQ ID NO:75), YFSVEAQ (SEQ ID NO:76), YFSVEAQT (SEQ ID NO:77) and YFSVEAQTG (SEQ ID NO:78); or (b) an analogue of any of the foregoing sequences that differs in one or more substitutions, deletions, additions and/or insertions such that that ability of the analogue to modulate an OB-cadherin-mediated function is not substantially diminished. For example, the agent may comprise a linear peptide having the sequence N-Ac-IFVIDDKSG-NH2 (SEQ ID NO:50), N-Ac-FFVIEEYTG-NH2 (SEQ ID NO:64) or N-Ac-YFSVEAQTG-NH2 (SEQ ID NO:78). The OB-cadherin CAR sequence may, but need not, be present within a cyclic peptide.
The present invention further provides antimetastatic agents that comprise an antibody or antigen-binding fragment thereof that specifically binds to an OB-cadherin CAR sequence and modulates OB-cadherin-mediated cell adhesion.
Within further aspects, the present invention provides antimetastatic agents comprising a non-peptide mimetic of an OB-cadherin CAR sequence.
Any of the above antimetastatic agents may, within certain embodiments, be linked to one or more of a drug, detectable marker, targeting agent or support material. Alternatively, or in addition, an antimetastatic agent as described above, may further comprise one or more of: (a) a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin; and/or (b) an antibody or antigen-binding fragment thereof that specifically binds to a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin. For example, such an adhesion molecule may be cadherin-5, cadherin-6, occludin, claudin, N-CAM, PE-CAM, CEA, L1, JAM, an integrin or N-cadherin.
Within other aspects, the present invention provides pharmaceutical compositions comprising an antimetastatic agent as described above in combination with a physiologically acceptable carrier. Within such compositions, the antimetastatic agent may, but need not, be present within a sustained-release formulation. Such compositions may, within certain embodiments, further comprise a drug and/or a modulator of cell adhesion that comprises one or more of: (a) a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin; and/or (b) an antibody or antigen-binding fragment thereof that specifically binds to a CAR sequence that is specifically recognized by an adhesion molecule other than OB-cadherin.
The present invention further provides, within other aspects, methods for inhibiting cancer metastasis. Such methods generally comprise administering to a patient an antimetastatic agent as described above, or a polynucleotide encoding such an agent. The patient may be afflicted with a cancer such as a carcinoma, leukemia or melanoma, and the antimetastatic agent may be administered to the tumor or systemically. Within such methods, the antimetastatic agent may, but need not, be present within a pharmaceutical composition as recited above.
These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.